Concentration of autoantibodies to native 60‐kd ro/ss‐a and denatured 52‐kd ro/ss‐a in eluates from the heart of a child who died with congenital complete heart block

Reichlin, Morris; Brucato, Antonio; Frank, Mark Barton; Maddison, Peter J.; Mccubbin, Victoria R.; Wolfson‐Reichlin, Marianne; Lee, Lela A.

doi:10.1002/art.1780371120

Cited by 104 publications

(40 citation statements)

References 26 publications

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“…However, deposition of immune complexes containing anti-double-stranded DNA antibody subsets can induce renal failure (11,12), these antibodies may also deposit directly on the glomerular basement membrane, inducing proteinuria (13). On the other hand, deposition of antibodies to Ro/SSA ribonucleoprotein in fetal cardiac tissues is thought to be associated with congenital heart block (14,15), and autoantibody subsets to ribosomal P proteins have been shown to be able to penetrate into live cells and cause cellular dysfunction (16). Because elevated rates of spontaneous and induced chromosomal damage have been reported in certain autoimmune rheumatic diseases (17,18), deficient DNA repair was observed in chronic ulcerative colitis (19) and SLE (20,21), and defects in poly(ADP-ribose) synthesis have been described in lupus patients and their healthy biological relatives (22,23), we studied the possibility that autoantibodies to F1 and F2 zinc fingers inhibit the PARP catalytic activity and cause the observed pathogenic effects.…”

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confidence: 99%

Inhibition of Caspase-3-mediated Poly(ADP-ribose) Polymerase (PARP) Apoptotic Cleavage by Human PARP Autoantibodies and Effect on Cells Undergoing Apoptosis

Decker¹,

Isenberg²,

Muller³

2000

Journal of Biological Chemistry

105

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Autoantibodies directed to nuclear antigens are serological hallmarks of autoimmune rheumatic diseases such as systemic lupus erythematosus. Although much more is known about the molecular identity and functions of targeted self-antigens, with few exceptions, evidence that autoantibodies to these targets have a particular function and contribute directly to the pathological process is lacking. Here we show that human autoantibodies reacting with the zinc fingers of poly(ADP-ribose) polymerase involved in the recognition of damaged DNA totally prevent the cleavage of poly(ADP-ribose) polymerase by caspase-3, a process that normally occurs during early apoptosis. Furthermore, these antibodies, which are frequent in certain autoimmune rheumatic and bowel diseases, affect the characteristic features of apoptosis and increase cell survival ex vivo. This new observation is important, because failure to remove autoimmune or abnormal cells can give rise to prolonged autoimmune stimulation and tumor formation.Poly(ADP-ribose) polymerase (PARP 1 ; EC 2.4.2.30) is a 116-kDa nuclear enzyme that detects and binds DNA strand breaks produced by various genotoxic agents. DNA breaks activate PARP, which in turn catalyzes the synthesis of poly(ADPribose) from its substrate, the respiratory coenzyme NAD ϩ , at the site of breakage (1, 2). The ADP-ribose polymer is primarily attached to PARP itself (automodification) and to a few other acceptor proteins (heteromodification) involved in chromatin architecture and DNA metabolism, thus affecting their activity. The function of PARP is thought to be related to a number of nuclear processes that involve nicking and resealing of DNA strands, including transcription and DNA repair. PARP is probably associated with a multifunctional complex comprising factor x-ray cross-complementing-1, DNA polymerase ␤, and DNA ligase III, which are involved in the base excision repair pathway. PARP knock-out mice display a marked genomic instability and an extreme sensitivity to genotoxic agents (3, 4), and it has been shown that PARP-deficient cell lines performed very limited DNA repair during the first hours after DNA damage by alkylating agents (5).PARP has a modular organization (1) comprising an N-terminal DNA binding domain, which acts as a molecular nick sensor and contains two zinc finger motifs called F1 and F2, which are involved in the recognition of DNA breaks during DNA repair (6) and a bipartite nuclear localization signal, a central regulating segment, which contains the automodification site, and the C-terminal catalytic domain, which binds NAD ϩ (Fig. 1). The presence of IgG antibodies reacting with the N-terminal F1 and F2 zinc fingers (7, 8) and, in a very few cases, with the PARP catalytic domain (9) has been described in the serum of patients with various systemic autoimmune diseases. In particular, a high prevalence of antibodies reacting with synthetic peptides corresponding to zinc fingers F1 and F2 (residues 18 -59 and 122-165, respectively) was observed in patients with certain...

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confidence: 99%

Inhibition of Caspase-3-mediated Poly(ADP-ribose) Polymerase (PARP) Apoptotic Cleavage by Human PARP Autoantibodies and Effect on Cells Undergoing Apoptosis

Decker¹,

Isenberg²,

Muller³

2000

Journal of Biological Chemistry

105

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“…Although proof of pathogenicity is not definitive, accumulating evidence suggests that anti-SS-A/Ro antibodies contribute to the cardiac and tissue damage in NLE (4,(35)(36)(37). A molecular definition of the SS-A/Ro autoantigens has been provided by the cloning of cDNAs, but little is known about their biologic function other than binding to hY RNAs or their role in disease pathogenesis and tissue injury.…”

Section: Discussionmentioning

confidence: 99%

Defining a novel 75-kDa phosphoprotein associated with SS-A/Ro and identification of distinct human autoantibodies

Wang¹,

Buyon²,

Zhu³

et al. 1999

J. Clin. Invest.

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“…It has been suggested that these antibodies react with their corresponding antigens on the surface of the cells of the conduction system in the heart (Horsfall et al 1991). Although antiRo/SSA antibodies have been eluted from affected fetal cardiac tissue (Reichlin et al 1994), there is no reason to expect the expression of the Ro/SSA protein, a nucleoprotein, in the surface membrane of the cardiac cells. In that regard it is interesting to note that Miranda et al (1998) have shown that apoptotic human fetal cardiomyocytes express Ro and La anti-gens in the surface.…”

Section: The Neonatal Lupus Syndromementioning

confidence: 99%

Neonatal lupus syndrome: the heart as a target of the immune system

Garcia

Carvalho

2000

An. Acad. Bras. Ciênc.

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Neonatal lupus erythematosus (NLE) is an auto-immune disease related to systemic lupus erythematosus (SLE). Unlike SLE it is not a spontaneous syndrome but rather an acquired one. In NLE the most common disease manifestations are a transient cutaneous lesion and cardiac conduction disturbances. The cutaneous lesions and other non-cardiac manifestations of NLE are transient and disappear about six months after birth, at the time when maternal antibodies disappear from the neonatal circulation. This fact suggests that maternal antibodies may cross the placenta leading to an inflamatory reaction in the fetal tissues. NLE is the principal cause of atria-ventricular block, when it is not associated with congenital birth defects. All the clinical studies to date correlate the heart block in NLE with the presence of certain types of circulating maternal antibodies, against the Ro/SSA nuclear proteins, in the serum of the newborn. In this paper we discuss animal models that have been developed by our and others groups to study the participation of the anti-Ro/SSA antibodies in the pathogenesis of the cardiac conduction blockades that occur in NLE.

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Concentration of autoantibodies to native 60‐kd ro/ss‐a and denatured 52‐kd ro/ss‐a in eluates from the heart of a child who died with congenital complete heart block

Cited by 104 publications

References 26 publications

Inhibition of Caspase-3-mediated Poly(ADP-ribose) Polymerase (PARP) Apoptotic Cleavage by Human PARP Autoantibodies and Effect on Cells Undergoing Apoptosis

Inhibition of Caspase-3-mediated Poly(ADP-ribose) Polymerase (PARP) Apoptotic Cleavage by Human PARP Autoantibodies and Effect on Cells Undergoing Apoptosis

Defining a novel 75-kDa phosphoprotein associated with SS-A/Ro and identification of distinct human autoantibodies

Neonatal lupus syndrome: the heart as a target of the immune system

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